tbuckley/cabot-search huggingface dataset:
SURG-41. PROGNOSTIC IMPACT OF EXTENDED RESECTIONS IN IDH MUTANT LOWER-GRADE DIFFUSE GLIOMA: RESULTS FROM A VOLUMETRIC ANALYSIS
Authors: Christine Jungk, Mara Gluszak, Andreas von Deimling, Christel Herold-Mende, Philip Dao Trong, Andreas Unterberg
Journal: Neuro-Oncology (2023)

Abstract In IDH mutant (IDHmut) glioma, the prognostic impact of extended resections is still under debate. A potential outcome benefit may be influenced by the tumor’s molecular phenotype. Also, many studies lack objective quantitative assessment of residual tumor volume (RTV). Here, we analyzed the prognostic benefit of surgery in a molecularly defined cohort of patients harboring an astrocytoma or oligodendroglioma, IDHmut, WHO grade 2 and 3, for whom volumetric analysis of RTV was possible. Patient-, tumor- and treatment-related factors including pre- and post-operative MR FLAIR tumor volumes were correlated with progression-free (PFS) and overall (OS) survival. Confounders of resectability were analyzed by multiple linear regression. 206 patients treated at our institution over one decade were identified retrospectively. Mean age was 40.37 years. 105 patients suffered from IDHmut astrocytoma and 101 patients from oligodendroglioma. Resection (n = 185 patients; 89.8%) as opposed to biopsy was associated with prolonged PFS and OS in astrocytoma (p = 0.007; p = 0.038) and WHO grade 2 tumors (p = 0.012; p &amp;lt; 0.0001). In patients undergoing resection, median pre- and post-operative tumor volumes did not differ between tumor subtypes but were significantly larger in WHO grade 3 than 2 tumors (pre-operative: 71.3 vs. 28.8 cm3; RTV: 7.78 vs. 1.98 cm3). Median RTV of the complete cohort was 4.6 cm3. There was a stepwise improvement of outcome with decreasing RTV (PFS: p = 0.0003; OS: p = 0.0004; data given for quartiles), with the strongest effect observed for patients with no RTV (median PFS: undefined vs. 58 months; p = 0.007). In multivariable analysis, RTV independently predicted OS (p = 0.001; HR 1.012) but not PFS. Resectability was only influenced by pre-operative FLAIR tumor volume (p &amp;lt; 0.0001). In summary, a continuous association of RTV and outcome was observed, even at the highest levels of resection. This finding was more pronounced in astrocytoma. Thus, a maximal resection should be strived for whenever safely achievable.
NCOG-38. UNDERSTANDING GLIOMA IN LI-FRAUMENI SYNDROME: HIGHLIGHTING THE VALUE OF SCREENING AND GENE SEQUENCING
Authors: Hannah Padilla, Ivan Carabenciov, Joon Uhm, Bryan Neth
Journal: Neuro-Oncology (2023)

Abstract Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant disorder characterized by a germline mutation in the TP53 gene that confers an increased risk of developing cancers, including brain tumors. There is continued need to understand how LFS diagnosis impacts clinical management and outcomes of gliomas. We report the clinical course of two patients from our Neuro-Oncology. Patient 1 is a male who was diagnosed with a low-grade astrocytoma, IDH1 mutant at age 20 status post gross total resection. Given radiographic concern for tumor progression, he underwent re-resection 8 years later. Pathology showed gliosis with TP53-mutant cells. Next-generation sequencing (NGS) was positive a germline TP53 mutation, consistent with LFS. He is currently in surveillance 12 years after diagnosis without need for radiation or chemotherapy. Patient 2 is a female who was diagnosed with glioblastoma, IDH wildtype, MGMT promoter unmethylated at age 40. She was asymptomatic at the time of diagnosis as the tumor was found during routine screening. She underwent gross total resection, radiation with concurrent and adjuvant temozolomide. She is now 5 years from last treatment without recurrence. These cases illustrate the clinical spectrum of glioma in LFS. Both patients have had prolonged periods of survival without progression, even accounting for respective tumor type. Patient 1 was only diagnosed with LFS after radiographic concerns for progression. Using NGS to diagnosis LFS was clinically important, as previous reports have shown greater propensity for malignant transformation of low-grade glioma in LFS. Patient 2 was diagnosed with glioblastoma during screening and has had no recurrence. This highlights the value of early diagnosis and treatment of gliomas in patients with LFS, even if asymptomatic at discovery. Further research is needed to understand the clinical spectrum of glioma in LFS and to optimize the care of this unique patient population.
IMMU-03. UTILIZING IN SILICO SINGLE-CELL TRANSCRIPTOMIC AND TCR PROFILING FOR THE IDENTIFICATION AND ISOLATION OF TUMOR-REACTIVE TCR CLONOTYPES IN RECURRENT GLIOBLASTOMA PATIENTS
Authors: Alexander Lee, Lu Sun, Frances Chow, Janet Treger, Danielle Cook, Ely Porter, Xi Chen, Gilbert Herrera, Richard Everson, Linda Liau, Timothy Cloughesy, Willy Hugo, David Nathanson, Robert Prins
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive form of primary brain cancer with no current cure. Immunotherapies, such as checkpoint blockade and adoptive T cell therapy, have effectively treated other cancers, but in GBM, these therapies have shown limited efficacy. This may be partially due to a lack of infiltrating tumor-reactive T cell populations capable of eliminating the tumor. METHODS &amp; RESULTS We used single-cell RNA and TCRsequencing to examine the transcriptome and TCR repertoire of tumor-infiltrating T cells from a cohort of 32 recurrent GBM patients, 18 of whom had received neoadjuvant anti-PD-1 therapy. After dimensional reduction, we found that the cluster defined by T cell activation and exhaustion gene expression had the greatest number of expanded T cell clones and a transcriptomic profile similar to a previously published signature of tumor-reactive T cells. Focusing on a patient treated with neoadjuvant anti-PD-1 and a EGFRvIII Bispecific T cell engager therapy, we selected TCRs from T cells within the activated and exhausted cluster. Utilizing the PathFinder DNA Assembly technology developed by Rootpath, we generated a TCR library containing the selected TCRs and transduced the library into a fluorescent-reporter Jurkat line that measures T cell activation. We co-cultured the transduced Jurkats with the patient-derived gliomasphere, FACs sorted for activated Jurkats and performed TCR sequencing on the sorted cells. Six TCRs within the sorted population were over-represented relative to sorted T cells from control co-cultures, indicating their tumor reactivity. CONCLUSIONS In this study we provide a proof-of-concept framework for how incorporating silico single-cell analysis of a T cell’s transcriptome and TCR can be used to identity tumor-reactive T cells for potential downstream adoptive T cell therapies for patients with recurrent GBM.
DISP-01. THE IMPACT OF COVID-19 PANDEMIC ON THE HEALTHCARE DELIVERY OF RACIAL/ETHNIC MINORITIES WITH BRAIN METASTASIS BY FACILITY TYPE
Authors: Ping Zhu, Clark Chen
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVES Brain metastases (BM) are the most common form of adult brain cancer and one of the most devastating complications of cancer. We propose to characterize the effect of the pandemic on health care delivery for racial/ethnic underserved populations on BM care in general and stratifying by facility type. METHODS We utilized two national-scale datasets - the National Cancer Database (NCDB) and one of the largest COVID-19 real-time centralized data in the world - the National COVID Cohort Collaborative (N3C) database. Multivariable binary logistic regression models were performed to determine whether the pandemic (three-dimensional measures: pre-pandemic vs. during-pandemic, COVID-19 positivity, and density of COVID-19 prevalence) influence BM care delivery [including stereotactic radiosurgery (SRS), chemotherapy, and immunotherapy], especially for race/ethnicity minorities and patients receiving treatments at non-academic centers (NACs). RESULTS Compared to pre-pandemic years, the proportions of receiving BM care significantly decreased across all racial/ethnic groups during the pandemic using two nationwide datasets (NCDB: N=5238; N3C: N=13106), but non-white patients were still significantly less likely to undergo SRS than non-Hispanic whites (NHW) in N3C (total: aOR-0.76, p&amp;lt; 0.001; Black: aOR-0.78, p&amp;lt; 0.001, Hispanic: aOR-0.75, p=0.013; APAA: aOR-0.62, p=0.002) and NCDB (Black: aOR-0.78, p=0.006). Similarly, the odds of receiving chemotherapy for race/ethnicity minorities BM patients were significantly lower than NHW in N3C (Black: aOR-0.71, Hispanic: aOR-0.63, APAA: aOR-0.46, all p&amp;lt; 0.001) and NCDB (Black: aOR-0.86, p=0.028). Furthermore, such inequality in SRS receipt by race/ethnicity was exacerbated during the pandemic at NACs over academic centers (ACs) (esp. Hispanic vs. NHW at NACs: aOR-0.58, p=0.004; Hispanic vs. NHW at ACs: aOR-0.88, p=0.380) in NCDB. CONCLUSION Our study suggests that BM healthcare delivery has been significantly reduced in general during the pandemic, but racial/ethnic disparities in BM care and inequality in healthcare access by facility type still exist and have been even exacerbated.
QOL-21. TARGETING FEAR OF CANCER RECURRENCE IN GLIOMA: OPEN PILOT TRIAL RESULTS OF <i>FEARLESS IN NEURO-ONCOLOGY</i>
Authors: Ashlee Loughan, Sarah Braun, Autumn Lanoye, Alexandria Davies, Amber Fox, Chris Kleva, Giuliana Zarrella
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Individuals with glioma endorse fear of cancer recurrence (FCR), but existing interventions for FCR are not entirely translatable to neuro-oncology. We consulted international FCR experts and advisory boards comprised of neuro-oncology professionals, patients, and caregivers to assist in creating a 6-module psychotherapy targeting FCR in glioma patients and caregivers: FearLess in Neuro-Oncology. Intervention modules will be discussed in-depth. METHODS The ongoing telehealth FearLess pilot aims to enroll 24 participants (6 glioma patients, 6 caregivers, 6 dyads) with clinical levels of FCR. Participants complete pre- and post-intervention surveys in addition to an exit interview. Data collection includes rates of screening, enrollment, module duration, session satisfaction, and intervention recommendations. RESULTS Of the 32 individuals screened, 16 enrolled (patients n = 6; caregivers n = 4; dyads n = 3), to date. All enrolled participants completed baseline assessments, with 15 trial initiators. 100% of trial initiators completed post-intervention surveys. Administration of the 6-module intervention averages 10 weekly, 60-minute sessions necessary for completion. All FearLess intervention completers have found it beneficial (100%) and would recommend to others (100%). Two patients recommended a shorter intervention duration and two caregivers recommended a longer duration. Preliminary analyses show reductions in FCR severity for 10 of 11 completed participants (MFCRI Reduction = 27.1, range = 4-50). CONCLUSION FearLess study procedures and intervention appear to be acceptable, thus far. Recruitment feasibility has been variable; caregiver participation is the primary concern given that caregiver and dyad arms remain open to accrual while the patient-only arm achieved its enrollment goal relatively quickly. Additional feasibility data is needed in order to understand how to best recruit caregivers of individuals with glioma into a psychological intervention targeting FCR. Despite the recruitment challenge, some caregivers recommended increased intervention duration, reinforcing the need for support in this vulnerable population. Continued optimization of FearLess in Neuro-Oncology is encouraged prior to larger-scale trials.
CNSC-31. BESPOKE THREE- PHOTON MICROSCOPY AND ANALYSIS ENABLE DEEP INTRAVITAL BRAIN TUMOR IMAGING
Authors: Stella Soyka, Marc Schubert, Amr Tamimi, Emanuel Maus, Robert Denninger, Niklas Wißmann, Ekin Reyhan, Svenja Tetzlaff, Carlo Beretta, Michael Drumm, Julian Schroers, Alicia Steffens, Jordain Walshon, Katy McCortney, Sabine Heiland, Anna Golebiewska, Felix Kurz, Wolfgang Wick, Frank Winkler, Anna Kreshuk, Thomas Kuner, Craig Horbinski, Robert Prevedel, Varun Venkataramani
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma is the most common primary brain tumor with a poor prognosis due to its aggressive invasiveness, inevitable recurrence, and therapy resistance. One hallmark of the disease is its whole brain dissemination via preexisting brain structures like blood vessels or white matter tracts. While intravital glioblastoma imaging has been limited to the superficial cortical layers, we developed a method of three photon microscopy allowing the investigation of glioblastoma invasion and colonization in the white matter up to a depth of 1.2 mm over extended time periods. Our method, combining adaptive optics 3P imaging, customized deep learning- based denoising and machine learning segmentation, enables longitudinal volumetric multicolor imaging, being able to distinguish GBM cell signal from myelin structures as well as blood vessel signal. Thus, GBM cells and their interactions with and influence on the microenvironment within the white matter can be investigated longitudinally. We found that compared to cortical invasion, a majority of GBM cells in the corpus callosum are aligned with myelinated axonal tracts, showing the influence of the tumor microenvironment on GBM cell directionality. Also, we found that most GBM cells enter the corpus callosum via a perivascular route. We identified two blood vessel-related mechanisms that allow invasion orthogonal to the myelinated axonal tract direction. We discovered that white matter tract directionality did not change significantly in the early stages of GBM colonization. This might explain limitations of modern clinical imaging to depict white matter glioma infiltration. However, we found that the shape of THG discontinuities differs between GBM cells and other resident cells, which could potentially serve as an imaging biomarker. To summarize, this tailored three-photon microscopy methodology allows unprecedented intravital investigation of GBM invasion in the gray and white matter, enabling the discovery of novel (sub-)cellular mechanisms in cancer and its microenvironment deep in the brain.
CNSC-44. BIOLOGICAL PATTERN DISCOVERY IN GLIOBLASTOMA
Authors: Shamini Ayyadhury, Patty Sachamitr, Michelle Kushida, Nicole Park, Fiona Coutinho, Owen Whitley, Panagiotis Prinos, Cheryl Arrowsmith, Peter Dirks, Trevor Pugh, Gary Bader
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma(GBM - IDH wildtype) is an adult glioma, showing abysmal prognosis. Sequencing technologies show us the existence of a neurodevelopmental frame-work, upon which heterogeneous molecular patterns are overlaid. The tumor's functional capacity is the net result of extrinsic+intrinsic molecular factors interacting with each other. These factors affect how cells communicate and organize themselves into complex functional architectures that support their evolution, survival and resistance. Understanding the phenotypic significance of a tumor's architecture, will allow us to understand these processes and compute complex patterns in GBM that are "biologically-relevant". First, we showed, as a proof-of-concept, that "biologically-relevant" signatures are imprinted within the spatial organization of cells using spatial pixel analysis. We used a phase-contrast image dataset of glioblastoma stem cells grown in culture, imaged 4-12hrly, over 12-16 days. We applied 29 hand-engineered pixel features per image, deriving spatial pixel signatures for each of our 17’601 phase-contrast images. Using different computational analytical methods and gene expression from matched bulk RNA datasets, we showed that spatial pixel patterning follows biologically relevant phenotypes. We found samples of images with high PC2 scores had higher mesenchymal/microglia scores, as compared to samples of images with low PC2 scores, which showed higher neurodevelopmental signatures. In addition, we found that mathematical algorithms describing entropy, homogeneity, contrast and complexity were clearly enriched in specific biological groups. Hence, our study showed that the organizational/architectural patterns of biological entities show preservation of fundamental organizational principles. Building upon the above data (which is currently a manuscript under preparation), we will apply these principles towards pattern discovery of GBM tissues at multiple architectural hierarchies (i.e subcellular, cellular, stroma) using different GBM models, imaging and spatial transcriptomics. If structure equates to function, understanding GBM architecture will have important applications in surgical tool developments and understanding relevant mechanistic patterns in GBM.
CTNI-30. MESENCHYMAL STEM CELL (MSC11FCD) BASED THERAPY ELICITED A FAVORABLE RESPONSE WITH EFFICIENT 5-FU CONVERSION IN PATIENTS WITH RECURRENT GLIOBLASTOMA: AN OPEN LABEL, PHASE I/IIA TRIAL
Authors: Jaejoon Lim, Da-Young Chang, Jeongmin Sim, Jin-Hwa Jung, JeongMan Park, Yu Jin Kim, Dongkil Kim, Sojung Hwang, Sung-Soo Kim, Hea-Young Cho, Haeyoung Suh-Kim, Kyunggi Cho
Journal: Neuro-Oncology (2023)

Abstract Mesenchymal stem cells (MSC) are being developed as therapeutic agents for treatment of various diseases due to their high tropism to damaged sites and cancers, and low immunogenicity. We are developing technologies to efficiently transfer therapeutic genes including suicide genes that will be used to suppress tumor growth or to ensure safety against possible adverse events and to develop off-the-shelf formulations for allogeneic uses. MSCs were engineered to express a suicide gene encoding non-human cytosine deaminase (CD) enzymes. We aimed to conduct a phase I/IIa clinical trial to investigate the maximum tolerated dose, safety, and efficiency of MSC11FCD in recurrent glioblastoma (GBM) patients. This study was a single-arm, open label, investigator-initiated trial on 10 patients recruited between 2021. The MSCs were administered via intra-tumoral injection after surgical resection. No severe adverse events and dose-dependent toxicities were observed. Median overall survival was not reached, and the median progression-free survival was over 4 months. We identified efficient 5-FU production and specific gene signature as biomarkers that predict response to MSC11FCD therapeutics in recurrent GBM, which might provide a new treatment strategy for this highly aggressive tumor. In conclusion, MSC11FCD therapy was safe and showed clinical efficiency in recurrent GBM patients. Specific gene signature can be used to screen individuals who might benefit from MSC11FCD therapy.
PATH-02. NOVEL <i>SOX10</i> INDEL MUTATIONS DRIVE SCHWANNOMAS THROUGH IMPAIRED TRANSACTIVATION OF MYELINATION GENE PROGRAMS
Authors: Erik Williams, Ajay Ravindranathan, Rohit Gupta, Nicholas Stevers, Abigail Suwala, Chibo Hong, Somang Kim, Jimmy Yuan, Jasper Wu, Jairo Barreto, Calixto-Hope Lucas, Emily Chan, Melike Pekmezci, Philip Leboit, Thaddeus Mully, Arie Perry, Andrew Bollen, Jessica Van Ziffle, W Patrick Devine, Alyssa T Reddy, Nalin Gupta, Kristen Basnet, Robert Macaulay, Patrick Malafronte, Han Lee, William Yong, Kevin Jon Williams, Tareq Juratli, Douglas Mata, Richard Huang, Matthew Hiemenz, Dean Pavlick, Garrett Frampton, Tyler Janovitz, Jeffrey Ross, Susan Chang, Mitchel Berger, Line Jacques, Jun Song, Joseph Costello, David Solomon
Journal: Neuro-Oncology (2023)

Abstract Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity due to their stereotypic intracranial and paraspinal locations. However, the molecular drivers responsible for a substantial subset remain unknown. Through genomic profiling of 96 schwannomas, we identified novel in-frame insertion/deletion mutations in the SOX10 gene in 29% of sporadic tumors which uniformly lacked alterations in known nerve sheath tumor genes including NF1, NF2, LZTR1, and SMARCB1. These indel mutations clustered at the C-terminal end of the HMG-box domain, the DNA binding motif of the SOX10 transcription factor critical for Schwann cell differentiation. Schwannomas arising from non-vestibular cranial nerves (e.g. facial, trigeminal, vagus) were highly enriched for SOX10 mutations, whereas the vast majority of vestibular schwannomas had NF2 inactivation. DNA methylation profiling revealed that SOX10 mutant schwannomas clustered together with schwannomas harboring NF2 mutation or SH3PXD2A-HTRA1 fusion, indicating that SOX10 indel mutations define a novel schwannoma molecular subtype and not a distinct nerve sheath tumor entity. To investigate the mechanism by which SOX10 indel mutations promote schwannoma development, we stably transduced human fetal glial cells with either wildtype SOX10 or two different tumor-derived insertion mutants. RNA sequencing revealed that both SOX10 indel mutants, in contrast to wildtype SOX10, failed to activate expression of myelination and glial differentiation gene programs, including PMP2 which encodes the major peripheral myelin protein in mature Schwann cells. Electrophoretic mobility shift assay revealed that the indel mutants retained their DNA binding capacity to the SOX10 binding site in the PMP2 promoter, while a luciferase reporter assay revealed transactivation at the PMP2 promoter by wildtype SOX10 but not by the mutants. In summary, we identified a new recurrent genetic event in 29% of sporadic schwannomas that we speculate drives schwannoma development through impaired transactivation of myelination gene expression programs causing blocked differentiation of immature Schwann cells.
IMMU-26. MRNA CAR T CELL TRAFFICKING FOLLOWING INTRA-VENTRICULAR ADMINISTRATION IN PRECLINICAL MODELS OF DIFFUSE MIDLINE GLIOMA
Authors: Zein Al-atrache, Olivia Mcmanus, Kyra Harvey, Conor Dickson, Luke Patterson, Ezra Beaubien, Cullen Wilson, Sreehita Hajeebu, Samantha Keil, Molly Braun, Michael Meechan, Nicholas Vitanza, Jeffrey Iliff, Peter Madsen, Jessica Foster
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND GD2-directed chimeric antigen receptor (CAR) T cells have shown promise as a potential therapeutic for diffuse midline glioma. We have previously shown intra-tumoral infusions of mRNA CAR T cells result in tumor regression with improved safety and toxicity profile in murine models. For human trials, the optimal route of CAR T cell administration into the central nervous system should maximize in vivo potency while minimizing procedural morbidity. Prior mRNA CAR T literature has reported decreased solid tumor infiltration with systemic delivery, so we sought to determine mRNA CAR T cell trafficking into pontine tumors from the cerebral spinal fluid to inform clinical translation of this therapy. METHODS Mice engrafted with SU-DIPG13P* tumor cells in the pons were treated with 5x106 mRNA CAR T cells into the lateral ventricle (LV) and brains were harvested 24 hours later. Tumor and T cells were analyzed using confocal microscopy to determine the migration of CAR T cells. RESULTS LV injection of GD2-directed CAR T cells resulted in T cell trafficking to the subarachnoid spaces, tumor site, and surrounding parenchyma. The highest concentration of T cells was in the subarachnoid space directly adjacent to the tumor (p&amp;lt; 0.0001) and decreased on a gradient to subcortical tumor. Even at 24 hours after injection, T cells were identified within the center of the tumor mass. CD19-directed control CAR T cells showed similar distribution within the subarachnoid with significantly decreased T cells at the tumor site. CONCLUSION Ventricular infusions of mRNA CAR T cells showed effective migration to pontine tumors within 24 hours. While CAR T cells did not fully penetrate the parenchyma within that timeframe, GD2-directed mRNA CAR T cells were detected within the center of the tumor mass, indicating ventricular administration may be sufficient for clinical delivery. Additional routes are being explored in ongoing work.